Stroke is the third largest cause of death and the leading cause of disability in the United States. The majority of strokes (80%) are ischemic and to date there has been limited therapeutic success in part because of single target treatment strategies ignoring the complex molecular and cellular events occurring after ischemia. Recent technological advances have allowed the analysis of large molecular expression databases and the consideration of novel parallel and time-specific therapeutic approaches in complex biologic systems. The Candidate is a neurosurgeon specializing in neurovascular and neuro-critical care, who proposes a career development plan as a clinician investigator with focused mentorship in molecular neurobiology, genomics, proteomics and bioinformatics. He proposes to study the molecular modulationof ion channels in the hours to days following hypoxia-hypoglycemia (HH) in relation to hippocampal neuronal cell death and also in association with the adaptive response known as ischemic tolerance. He has generated preliminary data demonstrating differential genomic expression of the Galanin receptor and proteomic expression of hippocalcin, both G-protein-linked receptors, and other potential sodium channel modulators in mouse hippocampal cultures exposed to HH. Sodium channel blockade is known to be neuroprotective and G-Protein receptor activation is known to result in sustained neuronal sodium currents, which may be associated with increased cell death. The proposed research will address the following hypotheses: Aim 1: There is a time-specific differential RNA and protein expression of ion channel modulators in the first 48 hours following ischemia; this is predicted to be critically distinct from expression changes following an initial conditioning exposure to sublethal HH, i.e. induction of ischemic tolerance. Aim 2: Ion channel modulators identified in Aim 1 can be experimentally manipulated to decrease hippocampal neuronal cell death by multiple mechanisms including the decrease of persistent sodium currents. The Candidate shall benefit from the coordinated mentorship of several leading investigators in a structured programmatic environment including core facilities for the proposed investigations. Results from this research will uncover new strategies for brain protection and ischemic therapy aimed at targeting of novel molecular pathways differentially involved in ischemic cell death and ischemic tolerance.